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PIC/S Guide for GMP and Data Integrity relating to microbiological quality Expectations for Microbiology Laboratories
Matt Davis Senior GMP Inspector Manufacturing Quality Branch
CAPSIG September 2018
• Regulatory Requirements: –PIC/S PE009-13 – Impact on Micro Labs
• Data Integrity
–PIC/S PI041-1 –DI in the laboratory
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Chapter 6 – Cross contamination
New Text: Comment
6.5 Control laboratory premises and equipment should meet the general and specific requirements for Quality Control areas given in Chapter 3. Laboratory equipment should not be routinely moved between high risk areas to avoid accidental cross-contamination. In particular, the microbiological laboratory should be arranged so as to minimize risk of cross-contamination.
Review the movement of all equipment into, within and out of the microbiology laboratory
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Chapter 6 – Documentation
New Text: Comment 6.7 iv. A procedure for the investigation of Out of Specification and Out Of Trend results; 6.9 Some kinds of data (e.g. tests results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any out of trend or out of specification data should be addressed and subject to investigation.
Need specific procedures for microbiology OOS/OOT investigation
6.8 Any Quality Control documentation relating to a batch record should be retained following the principles given in chapter 4 on retention of batch documentation.
QC record retention of expiry +1 year or 5 years, whichever is the longest
6.17 The tests performed should be recorded and the records should include at least the following data: ix. Reference to the equipment used.
Updates QC records to capture all equipment used in analysis
3
Chapter 6 – Trending of Data
New Text: Comment
6.16 The results obtained should be recorded. Results of parameters identified as critical quality attributes should be trended and checked to make sure that they are consistent with each other. Any calculations should be critically examined.
What data will be trended? Who is going to trend the data? Critical data trended as made available (Annex 15)
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Chapter 6 – Culture Media New Text: Comment 6.23 Culture media should be prepared in accordance with the media manufacturer’s requirements unless scientifically justified. The performance of all culture media should be verified prior to use.
QC of media required, for each batch made/supplied, before use
6.24 Used microbiological media and strains should be decontaminated according to a standard procedure and disposed of in a manner to prevent the cross-contamination and retention of residues. The in-use shelf life of microbiological media should be established, documented and scientifically justified.
Manage waste Need data for media shelf-life
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Chapter 6 – Method Verification/Tech Transfer
New Text: Comment
Testing 6.15 Testing methods should be validated. A laboratory that is using a testing method and which did not perform the original validation, should verify the appropriateness of the testing method. All testing operations described in the Marketing Authorisation or technical dossier should be carried out according to the approved methods.
Microbiological method validation required for all tests performed. Method transfer guidance in clauses 6.37 – 6.41 & Annex 15
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Chapter 7 - Outsourced activities Outsourced activities: • Training • Waste management • Outsourced engineering for facilities and equipment • Contract hire services • Suppliers of materials and components • Regulatory affairs consultants • Outsourced vendor auditing • Expert consultation • Certification • Calibration • Testing and analysis • Contract manufacture • cleaning
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So…..what’s data integrity?
“The extent to which all data are complete, consistent and accurate throughout the data lifecycle” from initial data generation and recording through processing (including transformation or migration), use, retention, archiving, retrieval and destruction. (PIC/S Good Practice for Data Management and Integrity PI 041-1)
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General issues observed
Contributing causes
Manipulation of data
No testing conducted
Not counting all colonies
OOL data not being investigated
Resampling/retesting without justification
Incomplete Testing
Samples not taken or “lost” in transit
No reconciliation of samples
Incubation conditions incorrect
Using unvalidated test methods
Poor test records Not recording all key test data
Worksheets ripped up and replaced
No reconciliation of forms used
Lack of proper computerised system security
Colony morphology not matching identification results
Competence/supervision Lack of effective controls Secondary Checks Computerised system configuration
Organisational Culture / resources
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Creating the right environment
• Data management controls embedded in PQS – System design to ensure good DI practices – QRM approach to data integrity – Ongoing risk review data criticality/risk – Self Inspection
• Clear understanding of importance of data integrity at all levels of the organisation
• Internal reporting is encouraged • Mature, open management approach to data integrity Rationalisation
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Designing Paper systems which reduce opportunities for falsification
Attributable
Legible / Permanent
Contemporaneous
Original Accurate
System design: documents in right place at right time,
clocks on wall, control of blank
forms
Signatures, Aliases;
signature logs
Workbooks, forms controlled,
verified ‘true copy’ scans
Reflective of the observation; Data checking, raw data
verification
No pencil, white-out, soluble ink,
SOP for corrections and
archiving
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Designing Electronic systems which reduce opportunities for falsification
Attributable
Legible / Permanent
Contemporaneous
Original Accurate
Auto-saving; step-wise recording;
System clock synchronisation
User access control; e-signatures; metadata
Metadata which permits
reconstruction
Data capture; manual data entry; source
data & audit trail review
Data security, audit trails;
back-up; sys. validation
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Risk management approach to Data Integrity Data
Criticality Data Risk • Data Criticality
– CQA Batch release data > cleaning records
– Data relating to product quality/safety • Data Risk
– Vulnerability of data to alteration, deletion, recreation, loss or deliberate falsification
• Outcome - Effective control strategy to manage identified risks
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DI controls – manual test methods
Sampling Procedures Sampling schedule/plans Training of technicians Sample forms Detailed collection methods Identity of sampler recorded
Test methods Test volumes/weights recorded Calibrated equipment used Reference to all reagents Reference to validated methods/dilution factors Samples processed under clean conditions, e.g. LAF Negative controls for processed samples Identity of tester/equipment recorded
Incubation Incubation records maintained Min/max incubation time defined and validated All transfers/sub-culturing recorded All incubated samples tagged and identified
Reading results Technicians trained in detection, enumeration and morphology – clear SOPs, photos Controlled environment for reading, light, magnification Counting device used for colonies Clear acceptance criteria/limits OOL & ID policy for manual recording All samples reconciled Results recorded Calculations applied correctly Second checks and verification in accordance with quality risk management
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A C
B
E D
Source: CDC Public Health Information Library
Encapsulated B. anthracis
E. Coli on blood agar
S. Aureus on MSA
A. Fumigatus
B. cereus on blood agar
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Electronic systems Validation
Software validation
Hardware qualification
Configuration management
Change management
Periodic system review
Configuration
Audit Trails
OS security
Data back-up/archiving
Test method configuration
User Access
SOPs for user access control
Individual user access
Defined user privileges
System administrator
Data management
Data review SOPs
Raw data verification
External calculation tools
Audit trail review
E-signatures
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Summary • Be aware of changes to PIC/S Guide to GMP
– Check TGA website for change summaries – Implement changes into your pharmaceutical quality systems
• Check TGA position on Data Management and Integrity – Review the PIC/S guidance for DMDI – Incorporate DI checks into internal and external self-inspection
programs • Notify the TGA of any significant DI findings
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Thank you for your attention
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